Protected aminothiazolylacetic acid derivatives

ABSTRACT

Described is a protected aminothiazolylacetic acid derivative represented by the following formula (I): ##STR1## wherein A represents a nitrogen atom or a methine group, R 1  and R 2  may be the same or different and individually represent a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aryl group, R 3  represents a lower alkoxy group, a halogenated lower alkoxy group, a triphenylmethoxy group, a lower alkyl group or an acyloxy group, and R 4  represents a halogen atom, a hydroxy group, a lower alkoxy group or a substituted or unsubstituted amino group; and salts thereof; as well as processes for the preparation thereof. The protected aminothaizolylacetic acid derivative according to the present invention is an useful intermediate for introducing a 2-(2-aminothiazol-4-yl)-2-alkoxyiminoacetyl group or a 2-(2-aminotiazol-4-yl)-2-alkenoyl group into a cephem skeleton.

This is a divisional application of Ser. No. 08/412,190, filed Mar. 28,1995.

BACKGROUND OF THE INVENTION

a) Field of the Invention

The present invention relates to protected aminothiazolyl acetic acidderivatives and salts thereof, which are preparation intermediatesuseful for introducing a 2-(2-aminothiazol-4-yl)-2-alkoxyiminoacetylgroup or a 2-(2-aminothiazol-4-yl)-2-alkenoyl group into a cephemskeleton, and also to a process for the preparation thereof. The abovealkoxyiminoacetyl group or alkenoyl group is a moiety common toantibiotics such as Cefmenoxime, Cefpodoxime proxetil, Cefepime,Cefpirome, Cefzopran, Cefclidine, DQ-2556 (CAS Registry No.102253-70-3), FK-037 (CAS Registry No. 122841-12-7), E1077 (CAS RegistryNo.116853-25-9), and S-1108 (CAS Registry No. 105889-45-0), and thelike.

b) Description of the Related Art

Antibiotics such as Cefmenoxime, Cefpodoxime proxetil, Cefepime,Cefpirome, Cefzopran, Cefclidine, DQ-2556, FK-037 and E1077 and the likecontain a 2-(2-aminothiazol-4-yl)-2-alkoxyiminoacetyl group or a2-(2-aminothiazol-4-yl)-2-alkenoyl group as a common moiety in theirmolecules. To obtain still higher antibacterial activities, thissubstituent is essential.

c) Prior Art

Upon introducing a 2-(2-aminothiazol-4-yl)-2-alkoxyiminoacetyl group ora 2-(2-aminothiazol-4-yl)-2-alkenoyl group into the cephem skeleton forthe preparation of an acid amide, it has heretofore been the practice touse an active derivative, such as an acid chloride, mixed acid anhydrideor active ester and the like of a2-(2-aminothiazol-4-yl)-2-alkoxyiminoacetic acid or a2-(2-aminothiazol-4-yl)-2-alkenoic acid, especially a2-(2-aminothiazol-4-yl)-2-alkoxyiminoacetyl chloride or a2-(2-aminothiazol-4-yl)-2-alkenoic acid chloride. Refer to JapanesePatent Application Laid-oepn Nos.123,189/87, 264,471/88, 264,470/88,156,984/89, and the like.

A conventional preparation process is shown by the following reactionsheme: ##STR2## wherein A represents a nitrogen atom or a methine group,R represents a lower alkoxy group, a halogenated lower alkoxy group, atriphenylmethoxy group, a lower alkyl group or an acyloxy group, and R'and R" individually represent a hydrogen atom or a substituent group.

Conventional active derivatives including2-(2-aminothiazol-4-yl)-2-alkoxyiminoacetyl chloride have nucleophilicreactivity, because the amino group on the thiazole ring is notprotected. Therefore, the active derivative is prepared or when theamino group is reacted with the cephem skeleton to form an acid amide, aside reaction takes place on the amino group, resulting in that ahigh-purity active derivative or acid amide could not be obtained in agood yield. Antibiotics, as pharmaceuticals, are required to haveparticularly high quality. In many cases, it is therefore necessary toconduct plural purification steps. The use of these active derivativestherefore has not been considered as an industrially suited preparationprocess.

To control the above-described side reaction on the amino group, it ispreferred to protect the amino acid in advance. A number of protectinggroups are known for the amino group. No protecting group is howeverknown to have stability in various reactions and readily removableproperty under mild conditions, as well as economical merits. Uponconducting a target investigation with a view toward inter aliaimproving the purity of a product, reducing its production cost andimproving the process operability, it was found that such conventionalamino-protecting groups are improper. In order to achieve the target,there has been desidered the development of a novel protectedaminothiazolylacetic acid derivative.

SUMMARY OF THE INVENTION

The inventors have proceeded with extensive research, with a view towarddeveloping a novel protected aminothiazolyl acetic acid derivative whichis useful in introducing a 2-(2-aminothiazol-4-yl)-2-alkoxyiminoacetylgroup or a 2-(2-aminothiazol-4-yl)-2-alkenoyl group into the cephemskeleton to prepare an acid amide and also permits an improvement in thepurity of the product, a reduction in the product cost, an improvementin the process operability and the like. As a result, it has been foundthat a protected aminothiazolyl acetic acid derivative represented bythe below-described formula (I) or a salt thereof can attain theabove-described object, leading to the completion of the presentinvention. ##STR3## wherein A represents a nitrogen atom or a methinegroup, R¹ and R² may be the same or different and individually representa hydrogen atom, a lower alkyl group or a substituted or unsubstitutedaryl group, R³ represents a lower alkoxy group, a halogenated loweralkoxy group, a triphenylmethoxy group, a lower alkyl group or anacyloxy group, and R⁴ represents a halogen atom, a hydroxyl group, alower alkoxy group or a substituted or unsubstituted amino group.

The present invention therefore provides a novel protectedaminothiazolylacetic acid derivative (I) or a salt thereof which isuseful for introducing a 2-(2-aminothiazol-4-yl)-2-alkoxyiminoacetylgroup or a 2-(2-aminothiazol-4-yl)-2-alkenoyl group which is a moietycommon to antibiotics such as Cefmenoxime, Cefpodoxime proxetil,Cefepime, Cefpirome, Cefzopran, Cefclidine, DQ-2556, FK-037 and E1077,and the like and also a process for the preparation thereof.

The present invention provides the following two processes for thepreparation of the protected aminothiazolyl-acetic acid (I) or the saltthereof:

(1) One process of route comprises reacting an aminothiazolylacetic acidderivative (II) represented by the following formula (II): ##STR4##wherein A, R³ and R⁴ have the same meanings as defined above, or a saltthereof with a (halogenated methylene)-dialkylammonium haliderepresented by the following formula (III): ##STR5## wherein R¹ and R²have the same meanings as defined above and X represents a halogen atom.

(2) The other process of route comprises effecting a reaction of anaminothiazolylacetic acid derivative (II) in a liquid mixture of aformamide derivative represented by the following formula (IV): ##STR6##wherein R¹ and R² have the same meanings as defined above, and achlorinating agent selected from phosphorus oxychloride, phosgene,diphosgene, triphosgene or oxalyl chloride.

The novel protected thiazolylacetic acid derivative (I) or the saltthereof according to the present invention has made it possible to meetthe requirements and desires described above.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

The protected aminothiazolylacetic acid derivative according to thepresent invention is represented by the following formula (I): ##STR7##wherein A represents a nitrogen atom or a methine group, R¹ and R² maybe the same or different and individually represent a hydrogen atom, alower alkyl group or a substituted or unsubstituted aryl group, R³represents a lower alkoxy group, a halogenated lower alkoxy group, atriphenylmethoxy group, a lower alkyl group or an acyloxy group, and R⁴represents a halogen atom, a hydroxy group, a lower alkoxy group or asubstituted or unsubstituted amino group.

In the above formula (I), the "methine group" in the definition for Ameans a group represented by the formula ═CH--. The "lower alkyl group"in the definitions for R¹, R², R³ and R⁴ may more specifically mean analkyl group having 1-6 carbon atoms, for example, a methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl or hexyl group andthe like. In the definition for R³, the "lower alkoxy group" may morespecifically mean a group formed of the above-described lower alkylgroup and an oxygen atom bonded therewith, such as a methoxy, ethoxy,propoxy, butoxy, pentyloxy or hexyloxy group, and the like. The"triphenylmethoxy group" means the group represented by the formula[--OC(C₆ H₅)₃ ], and the "acyloxy group" may more specifically mean agroup derived from a linear or branched fatty acid having 1-6 carbonatoms, for example, a formyloxy, acetoxy, propionyloxy, butyryloxy,valeryloxy or hexanoyloxy group and the like. The "halogen atom" in thedefinition for R⁴ may mean a chlorine, bromine, iodine or fluorine atom.The "halogenated lower alkoxy group" in the definition for R³, means theabove-described lower alkoxy group with some or all of its hydrogenatoms having been substituted by halogen atom(s), such as achloromethoxy, bromomethoxy, fluoromethoxy, difluoromethoxy,trifluoromethoxy, fluoroethoxy or fluoropropoxy group and the like. The"substituted or unsubstituted amino group" in the definition for R⁴,means, for example, an amino, methylamino, dimethylamino, ethylamino,diethylamino, propylethylamino, pyrrolidyl, piperidyl, anilino (--NH--C₆H₅), methylanilino (--NCH₃ --C₆ H₅), benzylamino (--NH--CH₂ C₆ H₅) orphenethylamino [--NH--CH₂ CH₂ C₆ H₅ or --NH--CH(CH₃)C₆ H₅ ] group andthe like. Among these, more preferred are a methyl or ethyl group for R¹and R², a methoxy, fluoromethoxy or trifluoromethoxy group for R³ when Ais a nitrogen atom; or an ethyl group for R³ when A is a methine group;and a hydroxy group or a chlorine or bromine atom for R⁴.

The protected aminothiazolylacetic acid derivative (i) includes, asshown below, a Syn-isomer (Z-isomer) and an Anti-isomer (E-isomer) asgeometric isomers with respect to an imino or methylidene grouprepresented by ═A˜R₃ in the formula (I). No particular limitation ishowever imposed on the isomerism in the present invention, so that theprotected aminothiazolylacetic acid derivative (I) can be one of thesegeometric isomers. ##STR8## wherein A, R¹, R², R³ and R⁴ have the samemeanings as defined above.

Further, the protected aminothiazolylacetic acid derivative (I) alsoincludes, as shown below, a Syn-isomer (Z-isomer) and an Anti-isomer(E-isomer) as geometric isomers with respect to an aminomethylidenaminogroup represented by R¹ R² N˜CH═N-- in the formula (I). No particularlimitation is however imposed on the isomerism in the present invention,so that the protected aminothiazolylacetic acid derivative (I) can beone of these geometric isomers. ##STR9## wherein A, R¹, R², R³ and R⁴have the same meanings as defined above.

In the protected aminothiazolylacetic acid derivative (I) according tothe present invention, the respective compounds have four geometricisomers depending upon the configuration of the imino group, methylidenegroup or aminomethylidenamino group. Needless to say, these isomers areall included in the present invention.

No particular limitation is imposed on the salt of the protectedaminothiazolylacetic acid derivative (I), insofar as it can be formed ina manner known per se in the art. Practical examples include additionsalts such as the hydrochloride, hydrobromide and hydroiodide and thelike.

The following compounds can be mentioned as more specific examples ofthe protected amiothiazolylacetic acid derivative (I), although theprotected aminothiazolylacetic acid derivative (I) in the presentinvention is not limited thereto.

(1) 2-(2-Dimethylaminomethylidenaminothiazol-4-yl)-2-methoxyiminoacetylchloride;

(2) 2-(2-Dimethylaminomethylidenaminothiazol-4-yl)-2-methoxyiminoacetylbromide;

(3) 2-(2-Dimethylaminomethylidenaminothiazol-4-yl)-2-methoxyiminoacetyliodide;

(4) 2-(2-Diethylaminomethylidenaminothiazol-4-yl)-2-methoxyiminoacetylchloride;

(5)2-(2-Dimethylaminomethylidenaminothiazol-4-yl)-2-trifluoromethoxyiminoacetylchloride;

(6) 2-(2-Dimethylaminomethylidenaminothiazol-4-yl)-2-methoxyiminoaceticacid;

(7)2-(2-Dimethylaminomethylidenaminothiazol-4-yl)-2-trifluoromethoxyiminoaceticacid;

(8) Methyl2-(2-dimethylaminomethylidenaminothiazol-4-yl)-2-methoxyiminoacetate;

(9) Butyl2-(2-dimethylaminomethylidenaminothiazol-4-yl)-2-methoxyiminoacetate;

(10)2-(2-Dimethylaminomethylidenaminothiazol-4-yl)-2-methoxyiminoacetamide;

(11)N-phenethyl-2-(2-dimethylaminomethylidenaminothiazol-4-yl)-2-methoxyiminoacetamide;

(12)2-[2-(N-Methyl-N-phenyl)aminomethylidenaminothiazol-4-yl]-2-methoxyiminoaceticacid;

(13)2-[2-(N-Methyl-N-phenyl)aminomethylidenaminothiazol-4-yl]-2-methoxyiminoacetylchloride;

(14) Ethyl2-[2-(N-methyl-N-phenyl)aminomethylidenaminothiazol-4-yl]-2-methoxyiminoacetate;

(15)2-[2-(N-Methyl-N-phenyl)aminomethylidenaminothiazol-4-yl]-2-methoxyiminoacetamide;

(16) 2-(2-Dimethylaminomethylidenaminothiazol-4-yl)-2-pentenoic acid;

(17) 2-(2-Dimethylaminomethylidenaminothiazol-4-yl)-2-pentenoylchloride;

(18) Ethyl 2-(2-dimethylaminomethylidenaminothiazol-4-yl)-2-pentenoate;

(19) 2-(2-Dimethylaminomethylidenaminothiazol-4-yl)-2-pentenoamide;

(20)2-[2-(N-Methyl-N-phenyl)aminomethylidenaminothiazol-4-yl]-2-pentenoicacid;

(21)2-[2-(N-Methyl-N-phenyl)aminomethylidenaminothiazol-4-yl]-2-pentenoylchloride;

(22) Ethyl2-[2-(N-methyl-N-phenyl)aminomethylidenaminothiazol-4-yl]-2-pentenoate;and

(23)2-[2-(N-Methyl-N-phenyl)aminomethylidenaminothiazol-4-yl)-2-pentenoamide.

An amiothiazolylacetic acid derivative (II) to be used in the presentinvention can be represented by the following formula (II): ##STR10##wherein A, R³ and R⁴ have the same meanings as defined above. Specificexamples of the aminothiazolylacetic acid derivative (II) include thefollowing compounds, although the aminothiazolylacetic acid derivative(II) in the present invention is not limited thereto.

(1) 2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetic acid;

(2) 2-(2-Aminothiazol-4-yl)-2-trifluoromethoxyiminoacetic acid;

(3) 2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetyl chloride;

(4) 2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetyl bromide;

(5) 2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetyl iodide;

(6) 2-(2-Aminothiazol-4-yl)-2-acethoxyiminoacetyl chloride;

(7) 2-(2-Aminothiazol-4-yl)-2-trifluoromethoxyiminoacetyl chloride;

(8) Methyl 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate;

(9) Butyl 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate;

(10) 2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamide;

(11) N-Phenethyl-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide;

(12) 2-(2-Aminothiazol-4-yl)-2-pentenoic acid;

(13) 2-(2-Aminothiazol-4-yl)-2-pentenoyl chloride;

(14) Ethyl 2-(2-aminothiazol-4-yl)-2-pentenoate; and

(15) 2-(2-Aminothiazol-4-yl)-2-pentenoamide.

A (halogenated methylene)-dialkylammonium halide to be used in thepresent invention can be represented by the following formula (III):##STR11## wherein R¹ and R² have the same meanings as defined above andX represents a halogen atom. Specific examples of the (halogenatedmethylene)-dialkylammonium halide (III) include the following compounds,although the (halogenated methylene)dialkylammonium halide (III) in thepresent invention is not limited thereto.

(1) (Chloromethylene)dimethylammonium chloride [popular name: Arnold'sreagent];

(2) (Bromomethylene)dimethylammonium bromide;

(3) (Chloromethylene)dimethylammonium chloride;

(4) (Bromomethylene)diethylammonium bromide; and

(5) (Chloromethylene)methylphenylammonium chloride.

These (halogenated methylene)-dialkylammonium halides (III) areavailable as organic synthesis reagents or industrial raw materials(products of SNPE Inc.), and can also be synthesized by the processdisclosed, for example, in "Chemical Industry",16, 664-5, 1972 or"Nucleic Acid Chemistry", vol. 2, 989-92 (1978), John Wiley & Sons,Inc., New York, N.Y., U.S.A.

The formamide derivative to be used in the present invention isrepresented by the following formula (IV): ##STR12## wherein R¹ and R²have the same meanings as defined above. Specific examples of theformamide derivative (IV) include the following compounds, although theformamide derivative (IV) in the present invention is not limitedthereto.

(1) N,N-dimethylformamide;

(2) N,N-diethylformamide;

(3) N-ethyl-N-propylformamide;

(4) N,N-dipropylformamide;

(5) Formamide; and

(6) N-methylformanilide.

The process of the present invention for the preparation of theprotected aminothiazolylacetic acid derivative (I) will hereinafter bedescribed in detail. The process can be practiced either in thefollowing two process of routes (1) and (2). In whichever route theprocess is carried out, the protected aminothiazolylacetic acidderivative (I) can be obtained.

(1) The aminothiazolylacetic acid derivative (II) or a salt thereof isreacted with the (halogenated methylene)-dialkylammonium halide (III).

(2) The aminothiazolylacetic acid derivative (II) or a salt thereof isreacted in a liquid mixture selected from the following combinations:

formamide derivative (IV) and phosphorus oxychloride;

formamide derivative (IV) and phosgene;

formamide derivative (IV) and diphosgene,

formamide derivative (IV) and triphosgene; or

formamide derivative (IV) and oxalyl chloride.

Here, the term "diphosgene" means trichloromethyl chloroformate (CASRegistry No. 503-38-8) represented by the following chemical formula:##STR13##

It is available as a regent or an industrial raw material. Further, theterm "triphosgene" means di-trichloromethyl carbonate (CAS Registry No.32315-10-9) represented by the following chemical formula: ##STR14## Itis available as a reagent or an industrial raw material. Alternativelyit can be synthesized according to the process disclosed in "Angew.Chem." 99 (9), 922-3, 1987.

Route (1)

In this route, the process can be practiced generally according to thepreparation process of an imine as disclosed in U.S. Pat. No. 4,652,644.In the present invention, it is preferred to dissolve a (halogenatedmethylene)-dialkylammonium halide (III) in a solvent and subsequent tothe addition of an aminothiazolylacetic acid derivative (II) or a saltthereof, followed by stirring the resulting mixture.

Although no particular limitation is imposed on the amount of the(halogenated methylene)-dialkyl-ammonium halide (III) to be used, it isused generally in an amount of 0.9-5.0 equivalents, preferably in anamount of 0.95-3.0 equivalents, more preferably in an amount of 1.0-2.0equivalents relative to the aminothiazolylacetic acid derivative (III).However, where the aminothiazolylacetic acid derivative (II) is acarboxylic acid (R⁴ ═OH), it is used generally in an amount of 1.9-10.0equivalents, preferably 1.95-6.0 equivalents, more preferably 2.0-2.0equivalents.

No particular limitation is imposed on the solvent insofar as it isinert to the (halogenated methylene)dialkylammonium halide (III) or theaminothiazolylacetic acid derivative (II). Specific examples ofgenerally usable solvents include tetrahydrofuran, 1,2-dimethoxyethane,ethyl ether, isopropyl ether, dioxane, dioxolan, methyl acetate, ethylacetate, propyl acetate, isopropyl acetate, butyl acetate, methylpropionate, ethyl butyrate, pyridine, chloroform, methylene chloride,dichloroethane, trichloroethane and the like. Of these, more preferredare, but are not limited to, tetrahydrofuran, methyl acetate andisopropyl ether. Although no particular limitation is imposed on theamount of the solvent to be used, the solvent is used generally in anamount of 1.0-50 ml, preferably 1.5-40 ml, more preferably 2.0-30 ml pergram of the (halogenated methylene)-dialkylammonium halide (III).

The reaction temperature is not limited either. The reaction can becarried out generally at from -78° C. to the refluxing temperature ofthe solvent. It is however preferred to conduct the reaction at atemperature of from -40° C. to room temperature, with a low temperatureof from -20° C. to 0° C. being more preferred.

Although the reaction time may vary depending on the amounts of the(halogenated methylene)-dialkyl ammonium halide (III) or the solvent tobe used and also on the reaction temperature, the reaction is generallycompleted within from 10 minutes to 3 hours or so.

Route (2)

In this route, the process can be practiced according to the methodgenerally known as the "Vilsmeyer reaction". In the present invention,however, it is preferred to add dropwise or blow a chlorinating agentselected from phosphorus oxychloride, phosgene, diphosgene, triphosgeneand oxazyl chloride into the formamide derivative (IV) under cooling,followed by, still under cooling, condition reacting the resultantliquid mixture with a solution of the aminothiazolylacetic acidderivative (II) or its salt.

Although no particular limitation is imposed on the amount of theformamide derivative (IV) to be employed in the present reaction, theformamide derivative (IV) is generally employed in an amount of 0.9-50equivalents, preferably 0.95-30 equivalents, more preferably 1.0-20equivalents relative to the aminothiazolylacetic acid derivative (II).No limitation is imposed on the amount of the chlorinating agent such asphosphorus oxychloride, and the like. The chlorinating agent can howeverbe used generally in an amount of 0.9-50 equivalents, preferably0.95-3.0 equivalents, more preferably 1.0-2.0 equivalents relative tothe aminothiazolylacetic acid derivative (II).

No particular limitation is imposed on the solvent insofar as it isinert to the formamide derivative (IV), the halogenating agent such asphosphorus oxychloride, and the like or the aminothiazolylacetic acidderivative (II). It is also possible to dispense with the other solventby using the formamide derivative (IV) in an excess amount. When asolvent is used, specific examples of generally usable solvents mayinclude tetrahydrofuran, 1,2-dimethoxyethane, ethyl ether, isopropylether, dioxane, dioxolan, chloroform, methylene chloride,dichloroethane, and trichloroethane and the like. Although no particularlimitation is imposed on the amount of the solvent, the solvent isemployed generally in an amount of 1.0-50 ml preferably 1.5-40 ml, morepreferably 2.0-30 ml per gram of the aminothiazolylacetic acidderivative (II).

The reaction temperature is not limited either. The reaction can becarried out generally at -78° C. to the refluxing temperature of thesolvent, preferably from -40° C. to room temperature, more preferablyfrom -20° C. to 10° C.

Although the reaction time may vary depending on the amounts of theformamide derivative (IV), the halogenating agent such as phosphorusoxychloride or the solvent to be used and also on the reactiontemperature, the reaction is generally completed within from 10 minutesto 6 hours or so.

The protected aminothiazolylacetic acid derivative (I) so obtained canbe isolated and purified by a method known per se in the art, forexample, by crystallization when it is in the form of an acid halide, orby recrystallization, silica gel column chromatography, HPLC or the likewhen it is a carboxylic acid, an ester or an acid amide.

Further, deprotection of the dimethylaminomethylidene group as aprotecting group to form an amino group can be conducted by hydrolyzingit under acidic or basic conditions.

EXAMPLES

The following examples are given to describe the present invention morepractically. Needless to say, the present invention is by no meanslimited by them.

EXAMPLE 1 Synthesis of(Z)-2-(2-dimethylaminomethylidenaminothiazol-4-yl)-2-methoxyiminoacetylchloride·hydrochloride ##STR15##

Dimethylaminochloromethyleneammonium chloride (496 mg, 3.87 mmol) wasdissolved in 10 ml of tetrahydrofuran, followed by cooling to -10° C.Added to the solution were 870 mg (3.4 mmol) of(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetyl chloride hydrochlorideand the resulting mixture was stirred for 40 minutes. The reactionmixture was concentrated under reduced pressure. Deposited crystals werecollected by filtration under a nitrogen gas stream and then dried atroom temperature, whereby 497 mg of the title compound were obtained(yield: 47%).

Syn-isomer

¹ H-NMR (DMSO-d₆, 400 MHz); δ (ppm): 8.68(1H,s), 7.56(1H,s), 3.91(3H,s),3.37(3H,s), 3.30(3H,s).

    ______________________________________                                        Elemental analysis:                                                                         Calculated                                                                              Found                                                 ______________________________________                                        H              3.89%     3.94%                                                C             34.74%    34.79%                                                N             18.00%    17.71%                                                ______________________________________                                        Quantitated amount of chlorine (ion chromatograph):                                  Calculated:                                                                           22.8%                                                                 Found:  23.1%                                                          ______________________________________                                    

EXAMPLE 2 Synthesis of(Z)-2-(2-dimethylaminomethylidenaminothiazol-4-yl)-2-methoxyiminoacetylchloride·hydrochloride

Dimethylaminochloromethyleneammonium chloride (1.52 g, 12.0 mmol) wasdissolved in 7 ml of tetrahydrofuran, followed by cooling to -12° C.Added to the solution were 1.10 g (5.5 mmol) of(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid and the resultingmixture was stirred for 40 minutes. Isopropyl ether (16 ml) was added tothe reaction mixture, followed by stirring for 20 minutes. Depositedcrystals were collected under a nitrogen gas stream, collected byfiltration and then dried, whereby 1.65 g of the title compound wereobtained (yield: 96.9%).

EXAMPLE 3 Synthesis of(Z)-2-(2-dimethylaminomethylidenaminothiazol-4-yl)-2-methoxyiminoacetylchloride·hydrochloride

Dimethylformamide (1.6 g, 22 mmol) and 10 ml of tetrahydrofuran weremixed, to which 3.06 g (24 mmol) of oxalyl chloride were added dropwiseunder ice-cooling. After completion of the dropwise addition, theresulting mixture was stirred for further 10 minutes and was then cooledto -15° C. To the mixture so obtained, were added 2.0 g (10 mmol) of(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid and 10 ml oftetrahydrofuran, followed by stirring for 80 minutes. The reactionmixture was concentrated under reduced pressure. Slurry was collected byfiltration under a nitrogen gas stream and then dried at roomtemperature, whereby 1.32 g of the title compound were obtained (yield:43%).

EXAMPLE 4 Synthesis of (Z)-2-(2-dimethylaminomethylidenaminothiazol-4-yl)-2-methoxyiminoacetyl chloride·hydrochloride

Dimethylformamide (0.8 g, 11 mmol) was added to 9 ml of tetrahydrofuran,followed by ice-cooling. To the resulting mixture, 0.6 ml oftrichloromethyl chloroformate was added dropwise under ice-cooling.After stirring the resulting mixture for 30 minutes, the mixture wascooled to -10° C. (Z)-2-(2-Amino-thiazol-4-yl)-2-methoxyiminoacetic acid(840 mg, 4.2 mmol) was added and the mixture so obtained was stirred for2 hours. The mixture was added with 9 ml of isopropyl acetate, followedby stirring for 30 minutes. A precipitate was collected by filtrationunder a nitrogen gas stream and then dried at room temperature, whereby1.23 g of the title compound were obtained (yield: 94%).

EXAMPLE 5 Synthesis of methyl (Z)-2-(2-dimethylamino methyliden aminothiazol-4-yl)-2-methoxyiminoacetate ##STR16##

(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid (0.5 g, 2.5 mmol)was dissolved in 20 ml of tetrahydrofuran. Subsequent to the addition of0.72 g (9.9 mmol) of dimethylformamide, the resulting solution wascooled to 5° C. The solution was added with 1.52 g (9.9 mmol) ofphosphorus oxychloride and the resulting mixture was stirred for 3hours. Methanol (20 ml) was added to the reaction mixture, followed bystirring for 10 minutes. A 2 N aqueous solution of sodium hydroxide wasadded to the reaction mixture to adjust its pH to 7. The reactionmixture so obtained was extracted three times with 100 ml portions ofchloroform. The organic phases were combined and then dried. The solventwas distilled off under reduced pressure. The residue was purified bychromatography on a silica gel column, whereby 0.63 g of the titlecompound was obtained (yield: 94%).

Syn-isomer

¹ H-NMR (CDCl₃, 400 MHz); δ (ppm): 8.30(1H,s), 6.99(1H,s), 4.00(3H,s),3.90(3H,s), 3.07(3H,s), 3.03(3H,s). FAB-MS: 271(MH⁺).

EXAMPLE 6 Synthesis of methyl(Z)-2-(2-dimethylaminomethylidenaminothiazol-4-yl)-2-methoxyiminoacetate

Dimethylaminochloromethyleneammonium chloride (400 mg, 3.1 mmol) wasdissolved in 10 ml of tetrahydrofuran, followed by cooling to -3° C. Thesolution was added with 300 mg (1.5 mmol) of(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid and the mixture soobtained was stirred for 40 minutes. After the resulting mixture wasadded with 10 ml of methanol and was then stirred for 10 minutes at roomtemperature, the mixture was poured into 50 ml of a saturated aqueoussolution of sodium hydrogencarbonate. The mixture so obtained wasextracted four times with 20 ml portions of chloroform. The extract wasdried over anhydrous magnesium sulfate. The dried matter was thenconcentrated under reduced pressure. The residue was purified bychromatography on a silica gel column, whereby 383 mg of the titlecompound were obtained (yield: 95%).

EXAMPLE 7 Synthesis of methyl(Z)-2-(2-dimethylaminomethylidenaminothiazol-4-yl)-2-acetoxyiminoacetate##STR17##

Dimethyiaminochloromethyleneammonium chloride (50 mg, 0.39 mmol) wasdissolved in 10 ml of tetrahydrofuran. Added to the resulting solutionwere 99 mg (0.35 mmol) of(Z)-2-(2-aminothiazol-4-yl)-2-acetoxyiminoacetyl·chloride hydrochloride,followed by stirring at room temperature for 40 minutes. Methanol (2 ml)was added thereto. The mixture so obtained was stirred for 10 minutes atroom temperature. The mixture was then poured into 50 ml of a saturatedaqueous solution of sodium hydrogencarbonate. The mixture so obtainedwas extracted four times with 20 ml portions of chloroform. The extractwas dried over anhydrous magnesium sulfate, and the dried matter wasthen concentrated under reduced pressure. The residue was purified bychromatography on a silica gel column, whereby 66 mg of the titlecompound were obtained (yield: 63%).

Syn-isomer

¹ H-NMR (CDCl₃, 400 MHz); δ (ppm): 8.33(1H,s), 7.42(1H,s), 3.98(3H,s),3.14(3H,s), 3.10(3H,s), 2.21(3H,s).

EXAMPLE 8 Synthesis of methyl(E)-2-(2-dimethylaminomethylidenaminothiazol-4-yl)-2-methoxyiminoacetate##STR18##

Dimethylaminochloromethyleneammonium chloride (400 mg, 3.1 mmol) wasdissolved in 10 ml of tetrahydrofuran, Added to the resulting solutionwere 300 mg of (Z)-2-(2-aminothiazol-4-yl)-2-methoxyimino-acetic acid,followed by stirring at room temperature for 16 hours. Methanol (10 ml)was added thereto. The mixture so obtained was stirred for 10 minutes atroom temperature. The mixture was then poured into 50 ml of a saturatedaqueous solution of sodium hydrogencarbonate. The mixture so obtainedwas extracted four times with 20 ml portions of chloroform. The extractwas dried over anhydrous magnesium sulfate. The dried matter was thenconcentrated under reduced pressure. The residue was purified bychromatography on a silica gelcolumn, whereby 293 mg of the titlecompound were obtained (yield: 72%).

Anti-isomer

¹ H-NMR (CDCl₃ 400 MHz); δ (ppm): 8.15(1H,s), 7.67(1H,s), 4.07(3H,s),3.89(3H,s), 3.07(3H,s), 3.06(3H,s).

EXAMPLE 9 Synthesis of methyl(Z)-2-(2-dimethylaminomethylidenaminothiazol-4-yl ) -2-pentenoate##STR19##

Dimethylaminochloromethyleneammonium chloride (830 mg, 6.5 mmol) wasadded to 12 ml of tetrahydrofuran, and the resulting mixture wasice-cooled. Added to the mixture were 196 mg (0.99 mmol) of(Z)-2-(2-aminothiazol-4-yl)-2-pentenoic acid, followed by stirring for 1hour. Methanol (10 ml) was added thereto. The mixture so obtained wasstirred for 30 minutes. The mixture was then poured into 60 ml of asaturated aqueous solution of sodium hydrogencarbonate. The mixture soobtained was extracted three times with 40 ml portions of ethyl acetate.The extract was dried over anhydrous magnesium sulfate and was thenfiltered. The filtrate was concentrated under reduced pressure. Theresidue was purified by chromatography on a silica gel column, whereby177 mg of the title compound were obtained (yield: 67%).

¹ H-NMR (CDCl₃, 400 MHz); δ (ppm): 8.22(1H,s), 7.05(1H,t,J=7.4 Hz),6.68(1H,s), 3.74(3H,s), 3.09(3H,s), 3.07(3H,s), 2.31(2H,t-q, J=7.4.-7.4Hz), 1.05(3H,t,J=7.4 Hz).

REFERENTIAL EXAMPLE 1 Synthesis of p-methoxybenzyl(+)-(6R,7R)-7-[(Z)-2-N,N-dimethylaminomethylidenaminothiazol-4-yl)-2-methoxyiminoacetamido]-3-chloromethyl-8-oxo-5-thia-azabicyclo[4,2,0]oct-2-ene-carboxylate##STR20##

Dimethylaminochloromethyleneammonium chloride (400 mg, 3.1 mmol) wasdissolved in 10 ml of tetrahydrofuran, followed by cooling to 3° C.Added to the resulting solution were 300 mg of(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid and the mixture soobtained was stirred for 2 hours. The resulting solution was added underice-cooling to a solution of 1.57 g (7.7 mmol) ofN,O-bis-trimethylsilylacetamide and 0.56 g (1.4 mmol) of p-methoxybenzyl7-amino-3-chloromethylcephalosporanoate in tetrahydrofuran, followed bystirring for 6 hours. After 50 ml of water were added, the pH of theresulting mixture was adjusted to 6 with a 2 N aqueous solution ofsodium hydroxide, followed by extraction with 50 ml of chloroform. Theaqueous phase was further extracted twice with 20 ml portions ofchloroform. The organic phases were combined and then dried overanhydrous magnesium sulfate. After the dried matter was filtered off,the matter was concentrated under reduced pressure. The residue wasdissolved in 50 ml of methanol and the resulting solution was washedthree times with 10 ml portions of n-hexane. The methanol phase wasconcentrated to dryness, whereby 0.97 g of the title compound wasobtained (purity: 76.4%).

FAB-MS: 607(MH⁺).

¹ H-NMR (CDCl₃, 400 MHz); δ (ppm): 8.29(1H,s), 7.44(1H,d,J=8 Hz),7.25(2H,d,J=8 Hz), 7.09(1H,s), 6.81(2H,d,J=8 Hz), 5.88(1H,dd,J=4,8 Hz),5.13(2H,s), 4.96(1H,d,J=4 Hz), 4.42(1H, d,J=12 Hz), 4.36(1H,d,J=12 Hz),3.97(3H,s), 3.72(3H,s), 3.59-3.36(2H,m), 3.00(3H,s), 2.96(3H,s).

REFERENTIAL EXAMPLE 2 Synthesis of 1-(isopropoxycarbonyloxy)ethyl(+)-(6R,7R)-7-[(Z)-2-N,N-dimethylaminomethylidenaminothiazol-4-yl)-2-acetoxyiminoacetamido]-3-N,N-dimethylcarbamoyloxymethyl-8-oxo-5-thia-azabicyclo[4,2,0]oct-2-ene-carboxylate##STR21##

Dimethylaminochloromethyleneammonium chloride (380 mg, 2.97 mmol) wasdissolved in 10 ml of tetrahydrofuran, followed by ice-cooling. Added tothe resulting solution were 760 mg (2.67 mmol) of(Z)-2-(2-aminothiazol-4-yl)-2-acetoxyiminoacetyl chloride hydrochlorideand the mixture so obtained was stirred for 1 hour. The resultingsolution was added under ice-cooling to a solution of 2.40 g (11.8 mmol)of N,O-bis-trimethylsilylacetamide and 1.22 g (2.61 mmol) of1-isopropoxycarbonyloxyethyl7-amino-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylatehydrochloride in tetrahydrofuran, followed by stirring for 6 hours.After 50 ml of water were added, the pH of the resulting mixture wasadjusted to 6 with a saturated aqueous solution of sodiumhydrogencarbonate, followed by extraction with 50 ml of ethyl acetate.The aqueous phase was further extracted twice with 50 ml portions ofethyl acetate. The organic phases were combined and then dried overanhydrous magnesium sulfate. After the dried matter was filtered off,the matter was concentrated under reduced pressure. The residue wasdissolved in 50 ml of methanol and the resulting solution was washedthree times with 10 ml portions of n-hexane. The methanol phase wasconcentrated to dryness, whereby 0.98 g of the title compound wasobtained (purity: 93.3%).

Syn-isomer diastereomer-1

¹ H-NMR(CDCl₃, 400 MHz); δ (ppm): 7.29(1H,d,J=8 Hz), 7.13(1H,s),6.76(1H,q,J=6 Hz), 5.85(1H,dd,J=4,8 Hz), 4.95-5.06(2H,m),4.71-4.81(2H,m), 3.47(1H,d,J=20 Hz), 3.38(1H,d,J=20 Hz), 3.00(3H,s),2.93(3H,s), 2.78(6H,s), 2.10(3H,s), 1.46(3H,d,J=6 Hz), 1.18-1.20(6H,m).

FAB-MS; 698 (MH⁺)

Syn-isomer diastereomer-2

¹ H-NMR(CDCl₃, 400 MHz); δ (ppm): 8.31(1H,d,J=8 Hz), 7.13(1H,s),6.86(1H,q,J=6 Hz), 5.85(1H,dd,J=4,8 Hz), 4.95-5.06(2H,m),4.71-4.81(2H,m), 3.47(1H,d,J=20 Hz), 3.38(1H,d,J=20 Hz), 3.00(3H,s),2.93(3H,s), 2.78(6H,s), 2.10(3H,s), 1.46(3H,d,J=6 Hz), 1.18-1.20(6H,m).

REFERENTIAL EXAMPLE 3 Synthesis of 1-(isopropoxycarbonyloxy)ethyl(+)-(6R,7R)-7-[(Z)-2-dimethylaminomethylidenaminothiazol-4-yl)-2-methoxyiminoacetamido]-3-N,N-dimethylcarbamoyloxymethyl-8-oxo-5-thia-azabicyclo[4,2,0]oct-2-ene-carboxylate ##STR22##

Dimethylaminochloromethyleneammonium chloride (300 mg, 2.3 mmol) wasdissolved in 10 ml of tetrahydrofuran, followed by ice-cooling. Added tothe resulting solution were 590 mg (2.3 mmol) of(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetyl chloride hydrochlorideand the mixture so obtained was stirred for 1 hour. The resultingsolution was added under ice-cooling to a solution of 1.90 g (9.4 mmol)of N,O-bis-trimethylsilylacetamide and 1.0 g (2.1 mmol) of1-isopropoxycarbonyloxyethyl7-amino-3-N,N-dimethyl-carbamoyloxymethyl-3-cephem-4-carboxylatemonohydrochloride in tetrahydrofuran, followed by stirring overnight.After 50 ml of water were added, the pH of the resulting mixture wasadjusted to 6 with a 2 N aqueous solution of sodium hydroxide, followedby extraction three times with 50 ml portions of ethyl acetate. Theorganic phases combined and then dried over anhydrous magnesium sulfate.After the dried matter was filtered off, the matter was concentratedunder reduced pressure. The residue was dissolved in 50 ml of methanoland the resulting solution was washed three times with 10 ml portions ofn-hexane. The methanol phase was concentrated to dryness, whereby 1.81 gof the title compound was obtained (purity: 66.8%).

Syn-isomer diastereomer-1

¹ H-NMR(CDCl₃, 400 MHz); δ (ppm): 8.35(1H,s), 7.32(1H,d,J=12 Hz),7.14(1H,s), 6.96(1H,q,J=6 Hz), 5.94(1H,dd,J=12,4 Hz), 5.15(1H,d,J=12Hz), 5.01(1H,d,J=4 Hz), 4.82(1H,d,J=12 Hz), 4.90-4.83(1H,m), 4.02(3H,s),3.55(1H,d,J=20 Hz), 3.44(1H,d,J=20 Hz), 3.06(3H,s), 3.01(3H,s),2.88(3H,s), 2.87(3H,s), 1.54(3H,d,J=6 Hz), 1.28(3H,d,J=6 Hz),1.26(3H,d,J=6 Hz).

Syn-isomer diastereomer-2

¹ H-NMR(CDCl₃, 400 MHz); δ (ppm): 8.35(1H,s), 7.17(1H,d,J=8 Hz),7.14(1H,s), 6.85(1H,q,J=6 Hz), 5.95(1H,dd,J=8,4 Hz), 5.06(1H,d,J=12 Hz),5.03(1H,d,J=4 Hz), 4.90(1H,d,J=12 Hz), 4.90-4.83(1H,m), 4.02(3H,s),3.56(1H,d,J=20 Hz), 3.44(1H,d,J=20 Hz), 3.06(3H,s), 3.01(3H,s),2.88(3H,s), 2.87(3H,s), 1.54(3H,d,J=6 Hz), 1.27(3H,d,J=6 Hz),1.26(3H,d,J=6 Hz).

REFERENTIAL EXAMPLE 4 Synthesis of 1-(isopropoxycarbonyloxy)ethyl(+)-(6R,7R)-7-[(Z)-2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-N,N-dimethylcarbamoyloxymethyl-8-oxo-5-thia-azabicyclo[4,2,0]oct-2-ene-carboxylate##STR23##

Dissolved in 3 ml of tetrahydrofuran were 40 mg of1-(isopropoxycarbonyloxy)ethyl(+)-(6R,7R)-7-[(Z)-2-dimethylaminomethylidenaminothiazol-4-yl)-2-methoxyiminoacetamido]-3-N,N-dimethylcarbamoyloxymethyl-8-oxo-5-thia-azabicyclo[4,2,0]oct-2-ene-carboxylatemonohydrochloride, followed by the addition of 0.5 ml of 1.8N sulfuricacid. The mixture so obtained was stirred for 3 days at roomtemperature. The reaction mixture was then added with 50 ml of water and50 ml of ethyl acetate. The resulting mixture was allowed to separateinto an organic phase and an aqueous phase. The aqueous phase wasadjusted to pH 7 with a saturated aqueous solution of sodiumhydrogencarbonate and then extracted twice with 30 ml portions Of ethylacetate. All the organic phases were combined, dried over anhydrousmagnesium sulfate and then concentrated under reduced pressure, wherebythe title compound was obtained (purity: 83.3%).

Syn-isomer diastereomer-1

¹ H-NMR(CDCl₃, 400 MHz); δ (ppm): 7.67(1H,d,J=9.0 Hz), 6.92(1H,q,J=5.4Hz), 6.72(1H,s), 5.96(1H,dd,J=4.9,9.0 Hz), 5.53(2H,br-s),5.12(1H,d,J=14.0 Hz), 5.00(1H,d,J=4.9 Hz), 5.14-5.00(1H,m),4.82(1H,d,J=14.0 Hz), 3.98(3H,s), 3.50(1H,d,J=18.8 Hz),3.43(1H,d,J=18.8Hz), 2.85(6H,s), 1.51(3H,d,J=5.4 Hz), 1.25(3H,^(d),J= 6 Hz),1.23(3H,d,J=6 Hz).

Syn-isomer diastereomer-2

¹ H-NMR(CDCl₃, 400 MHz); δ (ppm): 7.76(1H,d,J=9.0 Hz), 6.83(1H,q,J=5.4Hz), 6.72(1H,s), 5.99(1H,dd,J=4.9,9.0 Hz), 5.53(2H,br-s),5.06(1H,d,J=14.0 Hz), 5.01(1H,d,J=4.9 Hz), 5.14-5.00(1H,m),4.78(1H,d,J=14.0 Hz), 3.98(3H,s), 3.53(1H,d,J=18.8 Hz),3.43(1H,d,J=18.8z), 2.85(6H,s), 1.51(3H,d,J=5.4 Hz), 1.25(3H,d,J=6 Hz), 1.24(3H,d,J=6Hz).

REFERENTIAL EXAMPLE 5 Synthesis of(+)-(6R,7R)-7-[(Z)-2-N,N-dimethylaminomethylidenaminothiazol-4-yl)-2-methoxyiminoacetamido]-3-acetoxymethyl-8-oxo-5-thia-azabicyclo[4,2,0]oct-2-ene-carboxylic##STR24##

Dimethylaminochloromethyleneammonium chloride (1.14 g, 8.9 mmol) wasdissolved in 20 ml of tetrahydrofuran, followed by ice-cooling. Added tothe resulting solution were 590 mg (2.3 mmol) of(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetyl chloride hydrochlorideand the mixture so obtained was stirred for 1 hour. To the resultingsolution, a solution of 2.45 g (24.3 mmol) of triethylamine and 2.10 g(7.7 mmol) of 7-aminocephalosporanoic acid in tetrahydrofuran was added,followed by stirring for 6 hours under ice-cooling and further for 12hours at room temperature. Added to the resulting mixture was 1.0 g oftriethylamine, and the mixture so obtained was stirred for 3 hours.After 100 ml of a saturated aqueous solution of ammonium chloride wereadded, the pH of the resulting mixture was adjusted to 6 with aceticacid. The aqueous phase was then washed once with 100 ml of ethylacetate and further twice with 50 ml portions of ethyl acetate. Theaqueous phase was concentrated to about half its volume under reducedpressure. The concentrate was extracted once with 100 ml of methylenechloride and then twice with 50 ml portions of methylene chloride, andfurther once with 100 ml of ethyl acetate and then twice with 50mlportions of ethyl acetate. All the organic phases were combined, driedover anhydrous magnesium sulfate and concentrated under reducedpressure, whereby 1.9 g of the title compound was obtained (yield: 48%,purity: 80.2%).

Syn-isomer

¹ H-NMR(CDCl₃, 400 MHz); δ (ppm): 8.41(1H,s), 7.21(1H,s), 7.18(1H,d,J=12Hz), 5.93(1H,dd,J=12, 4 Hz), 5.10(1H,d,J=4 Hz), 5.09(1H,d,J=12 Hz), 4.94(1H,d,J=12 Hz), 4.07 (3H,s), 3.55(1H,d,J=16 Hz), 3.30(1H,d,J=16 Hz),3.10(3H,s), 3.06(3H,s), 2.06(3H,s).

REFERENTIAL EXAMPLE 6 Synthesis ofN-(2-phenylethyl)-2-(2-dimethylaminomethylidenaminothiazol-4-yl)-2-methoxyiminoacetamide##STR25##

Dimethylaminochloromethyleneammonium chloride (430 mg, 3.36 mmol) wasdissolved in 15 ml of tetrahydrofuran. Added to the solution were 860 mg(3.36 mmol) of (Z)-2-(2-aminothiazol-2-yl)-2-methoxyiminoacetyl chloridehydrochloride, followed by stirring at room temperature for 1 hour. Tothe solution so obtained, a solution of 1.02 g (10.1 mmol) oftriethylamine and 0.35 g (2.9 mmol) of β-phenethylamine in 4 ml oftetrahydrofuran was added. The mixture so obtained was stirred for 2hours under ice-cooling and further for 15 hours at room temperature.The reaction mixture was added with 100 ml of water and then extractedthree times with 50 ml portions of chloroform. The organic phases werecombined, dried over anhydrous magnesium sulfate and then concentratedunder reduced pressure. The residue so obtained was purified bychromatography on a silica gel column, whereby 0.98 g of the titlecompound was obtained (yield: 95%).

Syn-isomer

¹ H-NMR(CDCl₃, 400 MHz); δ (ppm): 8.33(1H,s), 7.31-7.19(5H,m),6.97(1H,s), 6.19(1H,s), 3.98(3H,s), 3.70(2H,q,J=8 Hz), 3.07(3H,s),3.03(3H,s), 2.06(2H,t,J=8 Hz).

FAB-MS: 360(MH⁺)

Anti-isomer

¹ H-NMR(CDCl₃, 400 MHz); δ (ppm): 8.07(1H,s), 7.75(1H,s), 7.64(1H,s),7.31-7.19(5H,m), 4.05(3H,s), 3.65(2H,q,J=8 Hz), 3.07(3H,s), 3.06(3H,s),2.91(2H,t,J=8 Hz.

FAB-MS: 360(MH⁺)

REFERENTIAL EXAMPLE 7 Synthesis of(Z)-N-(2-phenylethyl)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide##STR26##

(Z)-N-(2-phenylethyl)-2-(2-dimethylaminomethylidenaminothiazol-4-yl)-2-methoxyiminoacetamide(130 mg, 0.36 mmol) was dissolved in 4 ml of methanol, followed by theaddition of 0.5 ml of 1.8N sulfuric acid. The mixture so obtained wasstirred for 3 days at room temperature. The reaction mixture was thenadded with 20 ml of a saturated aqueous solution of sodiumhydrogencarbonate and 20 ml of ethyl acetate. The resulting mixture wasthen allowed to separate into an organic phase and an aqueous phase. Theaqueous phase was further extracted twice with 10 ml portions of ethylacetate. All the organic phases were combined, dried over anhydrousmagnesium sulfate and then concentrated under reduced pressure, whereby105 mg of the title compound were obtained (yield: 95%).

Syn-isomer

¹ H-NMR(CDCl₃, 400 MHz); δ (ppm): 7.35-7.20(5H,m), 6.73(1H,s),6.11(1H,s), 5.28(2H,br-s), 3.97(3H,s), 3.70(2H,dd,J=8,12 Hz),2.90(2H,t,J=8 Hz).

FAB-MS: 305(MH⁺)

REFERENTIAL EXAMPLE 8 Synthesis of(Z)-N-(2-phenylethyl)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide

(Z)-N-(2-Phenylethyl)-2-(2-dimethylaminomethylidenaminothiazol-4-yl)-2-methoxyiminoacetamide(130 mg, 0.36 mmol) was dissolved in 4 ml of methanol, followed by theaddition of 1 ml of 2 N hydrochloric acid. The mixture so obtained wasstirred at 60° C. for 3 hours and 30 minutes. The reaction mixture wasthen added with 20 ml of a saturated aqueous solution of sodiumhydrogencarbonate and 20 ml of ethyl acetate. The resulting mixture wasthen allowed to separate into an organic phase and an aqueous phase. Theaqueous phase was further extracted twice with 10 ml portions of ethylacetate. All the organic phases were combined, dried over anhydrousmagnesium sulfate and then concentrated under reduced pressure, whereby107 mg of the title compound were obtained (yield: 97.5%).

REFERENTIAL EXAMPLE 9 Synthesis of(Z)-N-(2-phenylethyl)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide

(Z)-N-(2-Phenylethyl)-2-(2-dimethylaminomethylidenaminothiazol-4-yl)-2-methoxyiminoacetamide(130 mg, 0.36 mmol) was dissolved in 4 ml of methanol, followed by theaddition of 0.5 ml of formic acid and 1 ml of water. The mixture soobtained was stirred at 60° C. for 3 hours and 30 minutes. The reactionmixture was then added with 20 ml of a saturated aqueous solution ofsodium hydrogencarbonate and 20 ml of ethyl acetate. The resultingmixture was then allowed to separate into an organic phase and anaqueous phase. The aqueous phase was further extracted twice with 10 mlportions of ethyl acetate. All the organic phases were combined, driedover anhydrous magnesium sulfate and then concentrated under reducedpressure, whereby 63 mg of the title compound were obtained (yield:57.9%).

REFERENTIAL EXAMPLE 10 Synthesis of(Z)-N-(2-phenylethyl)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide

(Z)-N-(2-Phenylethyl)-2-(2-dimethylaminomethylidenaminothiazol-4-yl)-2-methoxyiminoacetamide(130 mg, 0.36 mmol) was dissolved in 4 ml of methanol, followed by theaddition of 1 ml of a 1N aqueous solution of sodium hydroxide. Themixture so obtained was stirred at room temperature for 2 days. Thereaction mixture was then added with 20 ml of a saturated aqueoussolution of ammonium chloride and 20 ml of methylene chloride. Theresulting mixture was then allowed to separate into an organic phase andan aqueous phase. The aqueous phase was further extracted twice with 10ml portions of methylene chloride. All the organic phases were combined,dried over anhydrous magnesium sulfate and then concentrated underreduced pressure, whereby 90 mg of the title compound were obtained(yield: 81.8%).

What is claimed is:
 1. A process for the preparation of a protectedaminothiazolylacetic acid derivative or a salt thereof, said protectedaminothiazolylacetic acid derivative represented by the followingformula (I): ##STR27## wherein A represents a nitrogen atom or a methinegroup, R¹ and R² may be the same or different and individually representa hydrogen atom, a lower alkyl group or a substituted or unsubstitutedaryl group, R³ represents a lower alkoxy group, a halogenated loweralkoxy group, a triphenylmethoxy group, a lower alkyl group or anacyloxy group, and R⁴ represents a halogen atom, a hydroxy group, alower alkoxy group or a substituted or unsubstituted amino group, or asalt thereof, which process comprises:reacting an aminothiazolylaceticacid derivative represented by the following formula (II): ##STR28##wherein A, R³ and R⁴ have the same meanings as defined above, or a saltthereof, with a (halogenated methylene)-dialkylammonium haliderepresented by the following formula (III): ##STR29## wherein R¹ and R²have the same meanings as defined above and X represents a halogen atom.